Objective To explore the impact of peptidylarginine deiminase 2 ( Padi2 )-knockout on depressive-like behaviors in socially isolated mice. Methods Using CRISPR/ Cas9 technology, a Padi2-knockout (Padi2^{- / -}) mouse model with a C57BL / 6J background was established, and the effect of Padi2 knockout was identified by genotyping and RT-qPCR detection. Six-week-old male Padi2^{- / -} mice and wild-type C57BL / 6J mice were selected and divided into normal rearing and social isolation groups, with 15 mice per group. The normal rearing group mice were housed with 5 mice per cage, and the social isolation group was housed with 1 mouse per cage, and weighed once a week. After 4 weeks, forced swimming and open field tests were conducted. After the behavioral experiments, brain tissues were taken from mice in each group, and changes in microglia in the brains were detected by immunofluorescence. Results We successfully established Padi2^{- / -} mice. There was no difference in behavior between Padi2^{- / -}mice and C57BL / 6J mice in the normal rearing group. After social isolation, compared with C57BL / 6J mice, Padi2^{- / -}mice showed a significant increase in depressive symptoms, obvious weight gain, and a significant increase in the number of microglia in brain tissue. Conclusions Padi2 knockout exacerbated depressivelike behaviors and obesity in socially isolated mice, indicating that Padi2 is involved in the progression of depressionand may be an effective target for the prevention and treatment of depression.